Inborn errors of type I IFN immunity in patients with life-threatening COVID-19

doi:10.1126/science.abd4570

GSTDTAP > 气候变化

DOI	10.1126/science.abd4570
	Inborn errors of type I IFN immunity in patients with life-threatening COVID-19
	Qian Zhang; Paul Bastard; Zhiyong Liu; Jérémie Le Pen; Marcela Moncada-Velez; Jie Chen; Masato Ogishi; Ira K. D. Sabli; Stephanie Hodeib; Cecilia Korol; Jérémie Rosain; Kaya Bilguvar; Junqiang Ye; Alexandre Bolze; Benedetta Bigio; Rui Yang; Andrés Augusto Arias; Qinhua Zhou; Yu Zhang; Fanny Onodi; Sarantis Korniotis; Léa Karpf; Quentin Philippot; Marwa Chbihi; Lucie Bonnet-Madin; Karim Dorgham; Nikaïa Smith; William M. Schneider; Brandon S. Razooky; Hans-Heinrich Hoffmann; Eleftherios Michailidis; Leen Moens; Ji Eun Han; Lazaro Lorenzo; Lucy Bizien; Philip Meade; Anna-Lena Neehus; Aileen Camille Ugurbil; Aurélien Corneau; Gaspard Kerner; Peng Zhang; Franck Rapaport; Yoann Seeleuthner; Jeremy Manry; Cecile Masson; Yohann Schmitt; Agatha Schlüter; Tom Le Voyer; Taushif Khan; Juan Li; Jacques Fellay; Lucie Roussel; Mohammad Shahrooei; Mohammed F. Alosaimi; Davood Mansouri; Haya Al-Saud; Fahd Al-Mulla; Feras Almourfi; Saleh Zaid Al-Muhsen; Fahad Alsohime; Saeed Al Turki; Rana Hasanato; Diederik van de Beek; Andrea Biondi; Laura Rachele Bettini; Mariella D’Angio’; Paolo Bonfanti; Luisa Imberti; Alessandra Sottini; Simone Paghera; Eugenia Quiros-Roldan; Camillo Rossi; Andrew J. Oler; Miranda F. Tompkins; Camille Alba; Isabelle Vandernoot; Jean-Christophe Goffard; Guillaume Smits; Isabelle Migeotte; Filomeen Haerynck; Pere Soler-Palacin; Andrea Martin-Nalda; Roger Colobran; Pierre-Emmanuel Morange; Sevgi Keles; Fatma Çölkesen; Tayfun Ozcelik; Kadriye Kart Yasar; Sevtap Senoglu; Şemsi Nur Karabela; Carlos Rodríguez-Gallego; Giuseppe Novelli; Sami Hraiech; Yacine Tandjaoui-Lambiotte; Xavier Duval; Cédric Laouénan; COVID-STORM Clinicians†; COVID Clinicians†; Imagine COVID Group†; French COVID Cohort Study Group†; CoV-Contact Cohort†; Amsterdam UMC Covid-19 Biobank†; COVID Human Genetic Effort†; NIAID-USUHS/TAGC COVID Immunity Group†; Andrew L. Snow; Clifton L. Dalgard; Joshua D. Milner; Donald C. Vinh; Trine H. Mogensen; Nico Marr; András N. Spaan; Bertrand Boisson; Stéphanie Boisson-Dupuis; Jacinta Bustamante; Anne Puel; Michael J. Ciancanelli; Isabelle Meyts; Tom Maniatis; Vassili Soumelis; Ali Amara; Michel Nussenzweig; Adolfo García-Sastre; Florian Krammer; Aurora Pujol; Darragh Duffy; Richard P. Lifton; Shen-Ying Zhang; Guy Gorochov; Vivien Béziat; Emmanuelle Jouanguy; Vanessa Sancho-Shimizu; Charles M. Rice; Laurent Abel; Luigi D. Notarangelo; Aurélie Cobat; Helen C. Su; Jean-Laurent Casanova
	2020-10-23
发表期刊	Science
出版年	2020
英文摘要	The immune system is complex and involves many genes, including those that encode cytokines known as interferons (IFNs). Individuals that lack specific IFNs can be more susceptible to infectious diseases. Furthermore, the autoantibody system dampens IFN response to prevent damage from pathogen-induced inflammation. Two studies now examine the likelihood that genetics affects the risk of severe coronavirus disease 2019 (COVID-19) through components of this system (see the Perspective by Beck and Aksentijevich). Q. Zhang et al. used a candidate gene approach and identified patients with severe COVID-19 who have mutations in genes involved in the regulation of type I and III IFN immunity. They found enrichment of these genes in patients and conclude that genetics may determine the clinical course of the infection. Bastard et al. identified individuals with high titers of neutralizing autoantibodies against type I IFN-α2 and IFN-ω in about 10% of patients with severe COVID-19 pneumonia. These autoantibodies were not found either in infected people who were asymptomatic or had milder phenotype or in healthy individuals. Together, these studies identify a means by which individuals at highest risk of life-threatening COVID-19 can be identified. Science , this issue p. [eabd4570][1], p. [eabd4585][2]; see also p. [404][3] ### INTRODUCTION Clinical outcomes of human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection range from silent infection to lethal coronavirus disease 2019 (COVID-19). Epidemiological studies have identified three risk factors for severe disease: being male, being elderly, and having other medical conditions. However, interindividual clinical variability remains huge in each demographic category. Discovering the root cause and detailed molecular, cellular, and tissue- and body-level mechanisms underlying life-threatening COVID-19 is of the utmost biological and medical importance. ### RATIONALE We established the COVID Human Genetic Effort ([www.covidhge.com][4]) to test the general hypothesis that life-threatening COVID-19 in some or most patients may be caused by monogenic inborn errors of immunity to SARS-CoV-2 with incomplete or complete penetrance. We sequenced the exome or genome of 659 patients of various ancestries with life-threatening COVID-19 pneumonia and 534 subjects with asymptomatic or benign infection. We tested the specific hypothesis that inborn errors of Toll-like receptor 3 (TLR3)– and interferon regulatory factor 7 (IRF7)–dependent type I interferon (IFN) immunity that underlie life-threatening influenza pneumonia also underlie life-threatening COVID-19 pneumonia. We considered three loci identified as mutated in patients with life-threatening influenza: TLR3 , IRF7 , and IRF9 . We also considered 10 loci mutated in patients with other viral illnesses but directly connected to the three core genes conferring influenza susceptibility: TICAM1/TRIF , UNC93B1 , TRAF3 , TBK1 , IRF3 , and NEMO/IKBKG from the TLR3-dependent type I IFN induction pathway, and IFNAR1 , IFNAR2 , STAT1 , and STAT2 from the IRF7- and IRF9-dependent type I IFN amplification pathway. Finally, we considered various modes of inheritance at these 13 loci. ### RESULTS We found an enrichment in variants predicted to be loss-of-function (pLOF), with a minor allele frequency <0.001, at the 13 candidate loci in the 659 patients with life-threatening COVID-19 pneumonia relative to the 534 subjects with asymptomatic or benign infection ( P = 0.01). Experimental tests for all 118 rare nonsynonymous variants (including both pLOF and other variants) of these 13 genes found in patients with critical disease identified 23 patients (3.5%), aged 17 to 77 years, carrying 24 deleterious variants of eight genes. These variants underlie autosomal-recessive (AR) deficiencies ( IRF7 and IFNAR1 ) and autosomal-dominant (AD) deficiencies ( TLR3 , UNC93B1 , TICAM1 , TBK1 , IRF3 , IRF7 , IFNAR1 , and IFNAR2 ) in four and 19 patients, respectively. These patients had never been hospitalized for other life-threatening viral illness. Plasmacytoid dendritic cells from IRF7-deficient patients produced no type I IFN on infection with SARS-CoV-2, and TLR3−/−, TLR3+/−, IRF7−/−, and IFNAR1−/− fibroblasts were susceptible to SARS-CoV-2 infection in vitro. ### CONCLUSION At least 3.5% of patients with life-threatening COVID-19 pneumonia had known (AR IRF7 and IFNAR1 deficiencies or AD TLR3, TICAM1, TBK1, and IRF3 deficiencies) or new (AD UNC93B1, IRF7, IFNAR1, and IFNAR2 deficiencies) genetic defects at eight of the 13 candidate loci involved in the TLR3- and IRF7-dependent induction and amplification of type I IFNs. This discovery reveals essential roles for both the double-stranded RNA sensor TLR3 and type I IFN cell-intrinsic immunity in the control of SARS-CoV-2 infection. Type I IFN administration may be of therapeutic benefit in selected patients, at least early in the course of SARS-CoV-2 infection. ![Figure][5] Inborn errors of TLR3- and IRF7-dependent type I IFN production and amplification underlie life-threatening COVID-19 pneumonia. Molecules in red are encoded by core genes, deleterious variants of which underlie critical influenza pneumonia with incomplete penetrance, and deleterious variants of genes encoding biochemically related molecules in blue underlie other viral illnesses. Molecules represented in bold are encoded by genes with variants that also underlie critical COVID-19 pneumonia. Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)– and interferon regulatory factor 7 (IRF7)–dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection. [1]: /lookup/doi/10.1126/science.abd4570 [2]: /lookup/doi/10.1126/science.abd4585 [3]: /lookup/doi/10.1126/science.abe7591 [4]: https://www.covidhge.com [5]: pending:yes
领域	气候变化 ; 资源环境
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文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/300286
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Qian Zhang,Paul Bastard,Zhiyong Liu,et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19[J]. Science,2020.
APA	Qian Zhang.,Paul Bastard.,Zhiyong Liu.,Jérémie Le Pen.,Marcela Moncada-Velez.,...&Jean-Laurent Casanova.(2020).Inborn errors of type I IFN immunity in patients with life-threatening COVID-19.Science.
MLA	Qian Zhang,et al."Inborn errors of type I IFN immunity in patients with life-threatening COVID-19".Science (2020).